Diverse pathogens activate the host RIDD pathway to subvert BLOS1-directed immune defense

The phagocytosis and destruction of pathogens in lysosomes constitute central elements of innate immune defense. Here, we show that Brucella, the causative agent of brucellosis, the most prevalent bacterial zoonosis globally, subverts this immune defense pathway by activating regulated IRE1α- dependent decay (RIDD) of mRNAs encoding BLOS1, a protein that promotes endosome-lysosome fusion. RIDD-deficient cells and mice harboring a RIDD-incompetent variant of IRE1α were resistant to infection. Non-functional Blos1 struggled to assemble the BLOC-1-related complex (BORC), resulting in differential recruitment of BORC-related lysosome trafficking components, perinuclear trafficking of Brucella-containing vacuoles (BCVs), and enhanced susceptibility to infection. The RIDD-resistant Blos1 variant maintains the integrity of BORC and a higher-level association of BORC-related components that promote centrifugal lysosome trafficking, resulting in enhanced BCV peripheral trafficking and lysosomal-destruction, and resistance to infection. These findings demonstrate that host RIDD activity on BLOS1 regulates Brucella intracellular parasitism by disrupting BORC-directed lysosomal trafficking. Notably, coronavirus MHV also subverted the RIDD-BLOS1 axis to promote intracellular replication. Our work establishes BLOS1 as a novel immune defense factor whose activity is hijacked by diverse pathogens.

A Chlamydia trachomatis VD1-MOMP vaccine elicits cross-neutralizing and protective antibodies against C/C-related complex serovars

Ocular and urogenital infections with Chlamydia trachomatis (C.t.) are caused by a range of different serovars. The first C.t. vaccine in clinical development (CTH522/CAF®01) induced neutralizing antibodies directed to the variable domain 4 (VD4) region of major outer membrane protein (MOMP), covering predominantly B and intermediate groups of serovars. The VD1 region of MOMP contains neutralizing B-cell epitopes targeting serovars of the C and C-related complex. Using an immuno-repeat strategy, we extended the VD1 region of SvA and SvJ to include surrounding conserved segments, extVD1A and extVD1J, and repeated this region four times. The extVD1A*4 was most immunogenic with broad cross-surface and neutralizing reactivity against representative members of the C and C-related complex serovars. Importantly, in vitro results for extVD1A*4 translated into in vivo biological effects, demonstrated by in vivo neutralization of SvA and protection/cross-protection against intravaginal challenge with both SvA and the heterologous SvIa strain.

Intelligent Transportation Related Complex Systems and Sensors

Building around innovative services related to different modes of transport and traffic management, intelligent transport systems (ITSs) are being widely adopted worldwide to improve the efficiency and safety of the transportation system [...]

Expression of Spindle and Kinetochore-related Complex Subunit 3 is Associate With the Progression and Prognosis of Hepatocellular Carcinoma and Pancreatic Adenocarcinoma

Background Several studies have shown that Spindle and Kinetochore-related Complex Subunit 3 (SKA3) is closely related to the diagnosis and prognosis of various cancers. SKA3 plays a vital role in mitosis, but the mechanism underlying its action in tumors has not been fully elucidated. Methods Two separate microarrays of pancreatic adenocarcinoma (PAAD) and hepatocellular carcinoma (HCC) samples were downloaded from the Gene Expression Omnibus (GEO) and analyzed using R software. Tissues from 203 HCC and 321 PAAD patients were used for tissue microarray (TMA) construction and immunohistochemical staining for scoring. Kaplan-Meier estimators were used to determine their clinical relevance. Finally, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomics (KEGG) were used for analyzed rich pathways of SKA3 to understand gene function further. Results Contrary to the results obtained from the GEO database, HCC and PAAD tumor tissues exhibited significantly lower expression of SKA3 compared to the adjacent tissues (P < 0.001). The size of HCC tumor and Edmondson grade were statistically correlated with SKA3 expression (P < 0.05). No correlation was observed between the levels of SKA3 expression and vascular invasion, metastasis, or lymphatic infiltration in HCC patients. Moreover, factors related to decreases of SKA3 in PAAD could similarly not be found. Kaplan-Meier survival curves indicated that SKA3 upregulation in HCC was significantly associated with better prognosis (P = 0.016). In contrast, low levels of SKA3 were related to poor prognosis of PAAD patients (P = 0.026). Enrichment analysis of GO and KEGG pathways showed that SKA3 gene was closely related to cell cycle pathways. Conclusions The results of the present study indicate that SKA3 expression can serve as a diagnostic and prognostic biomarker for HCC and PAAD. However, there is a need to conduct further studies to verify these findings, especially the prognostic role of SKA3 in PAAD.